ABSTRACT The overarching goal of this Sexually Transmitted Infection Cooperative Research Center (STI CRC) proposal is to develop a candidate vaccine that provides significant protection against T. pallidum infection, the agent that causes syphilis. Despite susceptibility to penicillin, syphilis remains a public health threat worldwide, with an estimated 11 million new infections per year and a global burden of 36 million infections. In the last decade, there has been a resurgence of syphilis, with near doubling of rates among men who have sex with men and rates of congenital syphilis, resulting from mother to child transmission. As such, an effective prophylactic vaccine is required for control in addition to standard public health measures. The University of Washington has a long tradition of outstanding syphilis research: the research team assembled for this proposal has developed preclinical vaccine candidates that have substantial protection in the rabbit model. We propose three inter-related Scientific Projects. In Project 1, we will further refine the T. pallidum Tp0751 protein, which is essential for spread of T. pallidum through the bloodstream, for use as a vaccinogen by optimizing the protein formulation and the mode of delivery of this vaccinogen. In Project 2, we will optimize the TprK, and TprC/D2 proteins for vaccine use, as in animal models immunity to these antigens prevents chancre formation; optimization of these proteins will encompass protective epitope identification as well as optimal delivery of these epitopes. Subsequently, we will test the combined protective capacity of a vaccine cocktail comprised of these proteins in the syphilis rabbit model. In Project 3, we examine the B and T cell responses raised against the Tp0751 and Tpr vaccinogens in natural infection in humans and in vaccinated animals. As adjuvants that evoke immunity in rabbits differ from human-use adjuvants, we will also test the candidate vaccine adjuvanted with human track adjuvants in mouse immunogenicity studies as a prelude to human trials. The Scientific Projects will be supported by three Cores comprised of the Administrative Core, the Clinical and Statistical Core, and the Genomics and Isolation Core; the Developmental Research Project Program will provide mentoring and training to outstanding new investigators in the STI research field. By the end of the 5 year grant timeframe we propose to have a candidate vaccine that is ready for human trials.